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Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy: A Pooled Analysis From 2 Randomized Clinical Trials.

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Role of Deficient DNA Mismatch Repair Status

in Patients With Stage III Colon Cancer Treated

With FOLFOX Adjuvant Chemotherapy

A Pooled Analysis From 2 Randomized Clinical Trials

Aziz Zaanan, MD, PhD; Qian Shi, PhD; Julien Taieb, MD, PhD; Steven R. Alberts, MD, PhD; Jeffrey P. Meyers, PhD;

Thomas C. Smyrk, MD; Catherine Julie, MD; Ayman Zawadi, MD; Josep Tabernero, MD, PhD; Enrico Mini, MD, PhD; Richard M. Goldberg, MD, PhD; Gunnar Folprecht, MD, PhD; Jean Luc Van Laethem, MD, PhD;

Karine Le Malicot, PhD; Daniel J. Sargent, PhD; Pierre Laurent-Puig, MD, PhD; Frank A. Sinicrope, MD, PhD

IMPORTANCEThe prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial.

OBJECTIVETo determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX.

DESIGN, SETTING, AND PARTICIPANTSThe evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009.

INTERVENTIONS Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study.

MAIN OUTCOMES AND MEASURES Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status.

RESULTS Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P = .03).

CONCLUSIONS AND RELEVANCEThe deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy. TRIAL REGISTRATIONclinicaltrials.gov Identifier:NCT00079274for the NCCTG N0147 trial and EudraCT identifier:2005-003463-23for the PETACC8 trial.

JAMA Oncol. doi:10.1001/jamaoncol.2017.2899 Published online October 5, 2017.

Supplemental content

Author Affiliations: Author affiliations are listed at the end of this article.

Corresponding Author: Aziz Zaanan, MD, PhD, Department of

Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Paris Descartes University, Paris, France (aziz.zaanan@aphp.fr).

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A

djuvant trials have demonstrated that adding oxalipl-atin to fluorouracil is associated with improvement in survival of patients with stage III colon cancer, thereby establishing FOLFOX (folinic acid, fluorouracil, and oxalipl-atin) as the current standard of care.1A subset of colorectal can-cer (CRC) displays a microsatellite instability (MSI) pheno-type that is the consequence of deficient DNA mismatch repair (dMMR), due either to a germline mutation in an MMR gene, producing Lynch syndrome, or, more commonly, to epigen-etic inactivation of the MLH1 gene (OMIM120436) in spo-radic cases.2Somatic mutations in BRAF V600E are enriched in sporadic dMMR subtypes in contrast to a low frequency in CRCs overall.3

While most studies have found that patients with dMMR (vs proficient MMR [pMMR]) tumors have a more favorable stage-adjusted prognosis,4other studies have not detected a significant difference in clinical outcome5

or have suggested that any favorable prognostic effect of dMMR is limited to pa-tients with earlier-stage tumors.6Furthermore, studies have shown that dMMR tumors may not benefit from fluorouracil-based adjuvant chemotherapy.4However, the impact of MMR status remains controversial in the era of the standard FOLFOX adjuvant chemotherapy.

In a pooled analysis, we examined the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX from 2 phase 3 random-ized clinical trials: the trial of the North Central Cancer Treat-ment Group (NCCTG, now part of the Alliance for Clinical Trials in Oncology) N01477(Supplement 1) and the PETACC8 trial (Supplement 2).8

Methods

Study Population

This pooled analysis included all patient participants in the NCCTG N01477

and PETACC88

adjuvant randomized phase 3 trials who had signed biological informed consent and whose tumor blocks of resected stage III colon adenocarci-noma were available for analysis. Patients were randomized after surgery to receive 6 months of adjuvant FOLFOX t h e r a p y w i t h o r w i t h o u t c e t u x i m a b , a s d e s c r i b e d previously.7,8The present study is restricted to patients treated with FOLFOX alone, since the cetuximab did not improve efficacy in adjuvant setting.7,8

The NCCTG N0147 trial (NCT00079274) enrolled participants between February 2004 and November 2009; the PETACC8 trial (EudraCT 2005-003463-23) enrolled participants between December 2005 and November 2009. The molecular analysis was centralized at the Mayo Clinic, Rochester, Minnesota, for the NCCTG N0147 trial, and at the European Georges Pompidou Hospital, Paris, France, for the PETACC8 trial.

MMR Status Determination

Mismatch repair (MMR) tumor status was determined by im-munohistochemical analysis (IHC) or by MSI testing when IHC findings were indeterminate, as previously described for each trial.9,10Tumors with a dMMR phenotype were defined as

showing loss of expression of 1 or more MMR proteins by IHC or exhibiting high-level tumor DNA MSI on MSI testing by poly-merase chain reaction (PCR). Proficient MMR phenotype tu-mors were defined as showing intact MMR protein expres-sion on IHC or microsatellite-stable or low-level MSI status on MSI testing.

DNA Extraction and Mutation Analysis

Tumor DNA was extracted from formalin-fixed, paraffin-embedded tissue specimens containing more than 50% tu-mor cells using the QIAamp DNA Mini Kit (Qiagen). Testing for the BRAF V600E hotspot exon 15 mutation (c.1799T>A/ p.V600E) and KRAS exon 2 mutation was performed as de-scribed previously.9,10

Statistical Analysis

Biomarker status data were analyzed with investigators blinded to patient outcomes. We defined DFS as the time between ran-domization and local or metastatic recurrence, or death from any cause, whichever occurred first.

For comparisons of baseline characteristics, categorical fac-tors were analyzed with χ2tests, and continuous factors were compared with Wilcoxon rank-sum tests. A stratified Cox re-gression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and to calculate P values for can-didate prognostic factors.

Thereafter, multivariable analyses were performed on MMR phenotype adjusted for patient age, sex, tumor grade, ECOG (Eastern Cooperative Oncology Group) performance sta-tus, pT/pN stage, primary tumor location, and BRAF V600E mutational status. Survival curves were estimated with the Kaplan-Meier method and adjusted for the reported covariates.11Discriminatory accuracy was tested using the Harrell concordance index. The Harrell c index was used to estimate the proportion of correct predictions. The Harrell

c index ranges from 0.5 (no discrimination) to 1 (perfect

discrimination).

Two-sided P values are reported; P < .05 was considered statistically significant. Analyses were performed using SAS software, version 9.4 (SAS Institute Inc), on a data set locked on June 2015. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center.

Key Points

QuestionWhat is the role of deficient DNA mismatch repair (MMR) in stage III colon cancer in the era of standard FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant

chemotherapy?

FindingsThis pooled multivariable analysis of data from 2 randomized clinical trials revealed that deficient vs proficient MMR was significantly associated with longer disease-free survival in patients with stage III colon cancer who were treated with FOLFOX alone.

MeaningsFuture clinical trials in the adjuvant setting should consider MMR status as an important stratification factor.

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Results

Patients

Among 2636 patients with stage III colon cancer treated with

FOLFOX alone in the NCCTG N0147 (n = 1669)7

and PETACC88(n = 967) adjuvant therapy trials, MMR status was available for 2501 patients. Among this study population, 10.1% (252 of 2501) of tumors showed a dMMR phenotype (Figure 1). Consistent with prior studies, and with all sup-porting data reported in the Table, dMMR vs pMMR was significantly associated with older age, female sex, higher T stage, higher tumor grade, and proximal location.4As expected, mutations of BRAF V600E were more often asso-ciated with dMMR (36.9%) than with pMMR (6.3%) tumors (P < .001) (Table).6,12

The overall median follow-up was 4.0 years (interquartile range, 3.3-5.0 years).

Figure 1. Participant Enrollment Flowchart

2636 Patients treated with FOLFOX alone from NCCTG N0147 and PETACC8

2501 Patients tested for MMR status

2249 Proficient MMR 252 Deficient MMR 135 No informed consent for

translational research or unavailable material/technical failure

Included are participants in the NCCTG N01477

and PETACC88

phase 3 trials evaluating the impact of mismatch repair (MMR) phenotype in patients with stage III colon cancer treated with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy.

Table. Demographic and Clinicopathologic Characteristics of Stage III Colon Cancer Patients Treated With FOLFOX Arm From NCCTG N0147 and PETACC8 Trials

Characteristic MMR Status, No (%) P Value dMMR (n = 252) pMMR (n = 2249) Age, y Median 59.0 59.0 <70 208 (82.5) 1977 (87.9) .01 ≥70 44 (17.5) 272 (12.1) Sex .02 Female 134 (53.2) 1020 (45.4) Male 118 (46.8) 1229 (54.6) ECOG PS .42 0 192 (78.0) 1773 (79.8) 1 54 (22.0) 439 (19.8) ≥2 0 (0.0) 10 (0.5) pT stage .01 pT1-pT2 19 (7.5) 310 (13.8) pT3 185 (73.4) 1598 (71.1) pT4 48 (19.0) 341 (15.2) pN stage .27 pN1 160 (63.5) 1347 (59.9) pN2 92 (36.5) 902 (40.1) Tumor grade <.001 High 121 (48.4) 439 (19.6) Low 129 (51.6) 1800 (80.4) Tumor site <.001 Proximal 213 (86.2) 896 (40.5) Distal 34 (13.8) 1314 (59.5)

KRAS exon 2 status <.001

Wild-type 192 (77.1) 1289 (57.9)

Mutated 57 (22.9) 937 (42.1)

BRAF V600E status <.001

Wild-type 152 (63.1) 1994 (93.7)

Mutated 89 (36.9) 133 (6.3)

Abbreviations: dMMR, deficient MMR; ECOG PS, Eastern Cooperative Oncology Group performance status; MMR, Mismatch Repair;

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Association of MMR Status and Clinical Outcome

In this study population of patients with stage III colon can-cer treated with FOLFOX, there were 701 recurrences and 415 deaths. The 3-year DFS rates in dMMR and pMMR tumors were 75.6% and 74.4%, respectively. In multivariate analysis that in-cluded BRAF V600E mutational status, compared with the pMMR group, patients with dMMR tumor had a significantly longer DFS (adjusted HR, 0.73; 95% CI, 0.54-0.97; P = .03) (Harrell c index, 0.67; 95% CI, 0.64-0.70) (Figure 2).

Discussion

In the era of FOLFOX adjuvant chemotherapy, the first data concerning the impact of MMR status came from retrospec-tive studies suggesting that the addition of oxaliplatin to fluorouracil may confer survival benefit for patients with stage III dMMR colon cancer.13,14Thereafter, post hoc analy-ses of patients with stage II and III colon cancer (n = 1796)

from NSABP-C07 (comparing fluorouracil with and without oxaliplatin) and NSABP-C08 (comparing FOLFOX with and without bevacizumab) trials suggested that the benefit of adding oxaliplatin to fluorouracil was independent of MMR status.12Similarly, the analysis of MMR status in patients with stage II and III colon cancer (n = 1008) from the MOSAIC trial suggested that patients with both dMMR and pMMR tumors had a survival benefit from FOLFOX com-pared with fluorouracil alone, although the number of dMMR tumors analyzed was limited.15

In the present pooled analysis of patients with stage III co-lon cancer treated with FOLFOX in 2 adjuvant trials, we found that the dMMR phenotype was a favorable prognostic factor. Although the Harrell c index is of marginal clinical utility (<0.70), our study has several strengths that include prospec-tive tissue biospecimen collection and uniform tumor stage (III only) and treatment of patients enrolled in large recent ran-domized studies. Our report represents the largest study to date evaluating the relationship of MMR status with clinical out-come for FOLFOX adjuvant treatment. The relatively low ben-efit in terms of 3-year DFS rates (75.6% vs 74.4%) associated with a significant decrease in the risk of recurrence in multi-variate analysis (HR, 0.74) is related to the fact that our study is a post hoc and unplanned analysis with imbalanced sub-groups of patients (Table). Therefore, the unadjusted analy-sis highlights a survival benefit that may appear to be low but is actually clinically meaningful based on multivariate analy-sis that adjusts the results on clinical and pathological char-acteristics of these two groups.

Limitations

The main study limitation is the lack of mature follow-up to assess the overall survival.

Conclusions

In conclusion, this large pooled analysis showed that dMMR is a favorable prognostic factor in patients with stage III colon cancer treated with FOLFOX adjuvant chemotherapy. Future clinical trials in the adjuvant setting should consider this molecular characteristic as an important stratification factor.

ARTICLE INFORMATION

Accepted for Publication: July 3, 2017. Published Online: October 5, 2017. doi:10.1001/jamaoncol.2017.2899

Author Affiliations: Departments of Medicine and Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, Minnesota (Zaanan, Sinicrope); Paris Descartes University, Sorbonne Paris Cité, France (Zaanan, Taieb, Laurent-Puig); Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, APHP, Paris, France (Zaanan, Taieb); Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota (Shi, Meyers, Sargent); Department of Oncology, Mayo Clinic, Rochester, Minnesota (Alberts); Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota

(Smyrk); Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France (Julie); Versailles Saint-Quentin-en-Yvelines University, Boulogne-Billancourt, France (Julie); Radiotherapy Unit, Departemental Hospital Center, La Roche Sur Yon, France (Zawadi); Medical Oncology Department, Vall d‘Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain (Tabernero); Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (Mini); Division of Medical Oncology, Ohio State University, Columbus (Goldberg); First Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany (Folprecht); Department of Gastroenterology, Erasme Hospital University, Brussels, Belgium (Van Laethem); Department of

Statistics, Fédération Francophone de Cancérologie Digestive, Dijon, France (Le Malicot); UMR-S 1147, INSERM, Paris, France (Laurent-Puig); Department of Biology, European Georges Pompidou Hospital, APHP, Paris, France (Laurent-Puig).

Author Contributions: Drs Sinicrope and Taieb had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Zaanan, Shi, Taieb, Alberts,

Zawadi, Tabernero, Le Malicot, Sargent, Sinicrope.

Acquisition, analysis, or interpretation of data:

Zaanan, Shi, Taieb, Alberts, Meyers, Smyrk, Julié, Tabernero, Mini, Goldberg, Folprecht, Van Laethem, Le Malicot, Sargent, Laurent-Puig, Sinicrope.

Drafting of the manuscript: Zaanan, Taieb, Alberts,

Meyers, Julié, Zawadi, Tabernero, Van Laethem, Sargent, Laurent-Puig, Sinicrope.

Figure 2. Disease-Free Survival

0 No. at risk 0 2.0 3.0 4.0 5.0 100 90 Aliv e and Disease-F ree Patients, %

Years From Randomization 70 50 30 10 20 80 60 40 1.0 0.5 1.5 2.5 3.5 4.5 dMMR pMMR 229 196 172 148 90 54 2055 1845 1500 1224 719 329 dMMR pMMR MMR Status 0.73 (0.54-0.97) Reference Adjusted HR .03 P Value

Disease-free survival by MMR phenotype, deficient (dMMR) vs proficient (pMMR), in patients with stage III colon cancer treated with adjuvant FOLFOX (folinic acid, fluorouracil, and oxaliplatin). Survival curves and hazard ratio (HR) with 95% confidence intervals (CIs) are adjusted for age, sex, tumor grade, ECOG (Eastern Cooperative Oncology Group) performance status, pT/pN stage, primary tumor location, and BRAF V600E mutational status.

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Critical revision of the manuscript for important intellectual content: Zaanan, Shi, Taieb, Alberts,

Meyers, Smyrk, Julié, Tabernero, Mini, Goldberg, Folprecht, Van Laethem, Le Malicot, Sargent, Laurent-Puig, Sinicrope.

Statistical analysis: Shi, Meyers, Le Malicot. Obtained funding: Taieb, Alberts, Laurent-Puig,

Sinicrope.

Administrative, technical, or material support:

Zaanan, Alberts, Julié, Tabernero, Goldberg, Folprecht, Van Laethem, Le Malicot, Laurent-Puig, Sinicrope.

Supervision: Taieb, Zaanan, Alberts, Sargent,

Laurent-Puig, Sinicrope.

Conflict of Interest Disclosures: Dr Zaanan has participated in consulting and/or advisory boards for Roche, Merck Serono, Amgen, Sanofi and Lilly; Dr Taieb for Merck, Sanofi, Roche Genentech, Pfizer, and Amgen; Dr Julie for Roche and Merck Sereno; Mr Tabernero for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai Pharma, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho Pharmaceutical and Takeda; Mr Goldberg for Biothera, Sanofi and Merck; Dr Folprecht for Merck, Roche, Lilly, Bristol-Myers Squibb, Baxalta; Dr Sargent for Abbvie, Acerta Pharma, Ariad, Astellas Pharma, AstraZeneca, Biothera, Celldex, Exelixis, Genentech, Incyte, Kyowa Hakko Kirin, Medivation, Merck, Merrimack, Nektar, Novartis, Pharmacyclics, Pique, Spiration, Xbiotech, Celgene, Roche; Mr Laurent-Puig for Sanofi, Merck Serono, Amgen, Roche, Genomic Health, Myriad Genetics, and Pfizer; Dr Sinicrope for Illumina, Gilead, Ventana Medical Systems, EMD Serono, and Ventana Medical Systems. No other conflicts are reported.

Funding/Support: Dr Zaanan is supported by the “French National Society of Gastroenterology” (SNFGE: Société Nationale Française de Gastro-Entérologie) (Bourse Robert Tournut). The PETACC8 study was sponsored by the Fédération Francophone de Cancérologie Digestive (FFCD) that was responsible for the study management. Merck KGaA and Sanofi-Aventis supported the PETACC8 study: Merck provided the study cetuximab and financial support for study management; Sanofi-Aventis provided financial support for the provision of oxaliplatin to Belgian sites when necessary. The N0147 trial was conducted as a collaborative trial of the North Central Cancer Treatment Group (NCCTG), Mayo Clinic, which is now part of the Alliance for Clinical Trials in Oncology. The study was supported in part by grants from the US National Cancer Institute of the National Institutes of Health under Award Numbers U10CA025224, the NCCTG Biospecimen Resource (U24CA114740), and the Alliance for Clinical Trials in

Oncology (U10CA031946, U10CA033601, U10CA1808821 and U10CA180882). Bristol-Myers Squibb provided cetuximab to the NCCTG for conduct of the study. The present study was also supported in part by funds from Bristol-Myers Squibb, ImClone Systems Inc, Sanofi Aventis, and Pfizer.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The authors acknowledge the patient accrual contributions of the NCCTG N0147 and PETACC8 investigators and express their appreciation to the patients who participated in these clinical trials. Through this study, the authors would like to honor the memory of Dan Sargent for his great contributions to the entire cancer community worldwide. Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

REFERENCES

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2. Kawakami H, Zaanan A, Sinicrope FA. Implications of mismatch repair-deficient status on management of early stage colorectal cancer.

J Gastrointest Oncol. 2015;6(6):676-684. 3. Zaanan A, Bachet JB, André T, Sinicrope FA. Prognostic impact of deficient DNA mismatch repair and mutations in KRAS, and BRAF(V600E) in patients with lymph node-positive colon cancer.

Curr Colorectal Cancer Rep. 2014;10(3):346-353. 4. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.J Clin Oncol. 2010;28(20): 3219-3226.

5. Kim GP, Colangelo LH, Wieand HS, et al; National Cancer Institute. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute–National Surgical Adjuvant Breast and Bowel Project Collaborative Study.J Clin Oncol. 2007;25(7): 767-772.

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8. Taieb J, Tabernero J, Mini E, et al; PETACC-8 Study Investigators. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial.Lancet Oncol. 2014;15(8):862-873.

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10. Taieb J, Zaanan A, Le Malicot K, et al. Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: a post hoc analysis of the PETACC-8 Trial [published online January 14, 2016].

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12. Gavin PG, Colangelo LH, Fumagalli D, et al. Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value.Clin Cancer Res. 2012;18(23):6531-6541. 13. Tougeron D, Mouillet G, Trouilloud I, et al. Efficacy of adjuvant chemotherapy in colon cancer with microsatellite instability: a large multicenter AGEO study.J Natl Cancer Inst. 2016;108(7). 14. Zaanan A, Cuilliere-Dartigues P, Guilloux A, et al. Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin.Ann Oncol. 2010;21(4):772-780.

15. André T, de Gramont A, Vernerey D, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC Study.J Clin Oncol. 2015;33(35):4176-4187.

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